Project Summary/Abstract We have recently performed a vaccine trial using Mamu-B*17+ Indian rhesus macaques, which demonstrated remarkable control of chronic phase viral replication in five ?rapid controller? animals. Control correlated with the development of increased endpoint titers of vaccine-induced anti-gp140 binding antibodies (Abs) on day of challenge. These Abs did not neutralize the simian immunodeficiency virus mac239 (SIVmac239) clone. We have rarely seen this type of stringent control of SIVmac239 replication in more than 130 intrarectally (IR)-challenged macaques with the same dose of this stock of SIVmac239. In Specific Aim I, we will investigate whether the vaccine-induced Env-binding Abs in the Mamu-B*17+ ?rapid controller? animals either had direct anti-viral effects or facilitated the development of efficacious T-cell responses. We will address this hypothesis by utilizing two different approaches involving transfer of serum IgG and monoclonal antibodies (mAbs) from the ?rapid controller? animals to vaccinated and nave animals. We will also investigate the nature of control in Mamu-B*08+ Indian rhesus macaques. More than 50% of nave (no vaccine or drug treatment) Mamu-B*08+ macaques become ?elite controllers? (ECs) after infection with SIVmac239. In Specific Aim II, we will determine the genes involved in the control of the innate immune response that influence the development of elite control in macaques that express Mamu-B*08. It is becoming increasingly apparent that classical vaccine-induced CD8+ T-cells by themselves will not be sufficient to either prevent or control human immunodeficiency virus (HIV) or SIV infection. Recent studies have suggested that in conjunction with other effector molecules (Abs, innate immune responses) CD8+ T-cells can function effectively in the control of HIV/SIV replication in vaccinated individuals. Our studies plan to elucidate these mechanisms in two cohorts of macaques where unusual control of SIV replication has been observed.